PAX6

PAX6
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2CUE, 6PAX
Identifiers
Aliases	PAX6, AN, AN2, D11S812E, FVH1, MGDA, WAGR, paired box 6, ASGD5
External IDs	OMIM: 607108 MGI: 97490 HomoloGene: 1212 GeneCards: PAX6
Gene location (Human) Chr. Chromosome 11 (human)[1] Band No data available Start 31,784,779 bp[1] End 31,818,062 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band No data available Start 105,668,900 bp[2] End 105,697,364 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • protein binding • DNA binding • sequence-specific DNA binding • ubiquitin-protein transferase activity • RNA polymerase II core promoter proximal region sequence-specific DNA binding • RNA polymerase II core promoter sequence-specific DNA binding • RNA polymerase II transcription factor activity, sequence-specific DNA binding • transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding • transcriptional repressor activity, RNA polymerase II transcription regulatory region sequence-specific binding • transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific binding • chromatin binding • transcription factor activity, sequence-specific DNA binding • transcription factor binding • protein kinase binding • ubiquitin protein ligase binding • histone acetyltransferase binding • transcription regulatory region DNA binding • co-SMAD binding • R-SMAD binding • HMG box domain binding Cellular component • cytoplasm • nucleus • nucleoplasm • cytosol • nuclear chromatin • intracellular Biological process • eye development • blood vessel development • animal organ morphogenesis • regulation of transcription, DNA-templated • glucose homeostasis • transcription, DNA-templated • central nervous system development • response to wounding • cell differentiation • cornea development in camera-type eye • negative regulation of neurogenesis • visual perception • iris morphogenesis • multicellular organism development • neuron fate commitment • protein ubiquitination • negative regulation of transcription from RNA polymerase II promoter • establishment of mitotic spindle orientation • cell fate determination • neuron migration • negative regulation of protein phosphorylation • positive regulation of neuroblast proliferation • lens development in camera-type eye • regionalization • type B pancreatic cell differentiation • pancreatic A cell development • regulation of transcription from RNA polymerase II promoter • transcription from RNA polymerase II promoter • smoothened signaling pathway • axonogenesis • axon guidance • brain development • salivary gland morphogenesis • negative regulation of cell proliferation • regulation of asymmetric cell division • dorsal/ventral axis specification • anterior/posterior pattern specification • dorsal/ventral pattern formation • regulation of gene expression • positive regulation of gene expression • pallium development • oligodendrocyte cell fate specification • cerebral cortex regionalization • forebrain dorsal/ventral pattern formation • commitment of neuronal cell to specific neuron type in forebrain • forebrain-midbrain boundary formation • regulation of transcription from RNA polymerase II promoter involved in spinal cord motor neuron fate specification • regulation of transcription from RNA polymerase II promoter involved in ventral spinal cord interneuron specification • regulation of transcription from RNA polymerase II promoter involved in somatic motor neuron fate commitment • telencephalon regionalization • pituitary gland development • habenula development • signal transduction involved in regulation of gene expression • keratinocyte differentiation • regulation of cell migration • positive regulation of epithelial cell differentiation • forebrain development • lacrimal gland development • protein localization to organelle • eye photoreceptor cell development • camera-type eye development • cell fate commitment • negative regulation of neuron differentiation • positive regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter • regulation of timing of cell differentiation • embryonic camera-type eye morphogenesis • astrocyte differentiation • negative regulation of epithelial cell proliferation • regulation of neurogenesis • retina development in camera-type eye • cellular response to leukemia inhibitory factor • negative regulation of neural precursor cell proliferation Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	5080	18508
Ensembl	ENSG00000007372	ENSMUSG00000027168
UniProt	P26367	P63015
RefSeq (mRNA)	NM_000280 NM_001127612 NM_001258462 NM_001258463 NM_001258464 NM_001258465 NM_001310158 NM_001310159 NM_001310160 NM_001310161 NM_001604	NM_001244198 NM_001244200 NM_001244201 NM_001244202 NM_013627 NM_001310144 NM_001310145 NM_001310146
RefSeq (protein)	NP_000271 NP_001121084 NP_001245391 NP_001245392 NP_001245393 NP_001245394 NP_001297087 NP_001297088 NP_001297089 NP_001297090 NP_001595	NP_001231127 NP_001231129 NP_001231130 NP_001231131 NP_001297073 NP_001297074 NP_001297075 NP_038655
Location (UCSC)	Chr 11: 31.78 – 31.82 Mb	Chr 11: 105.67 – 105.7 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Paired box protein Pax-6, also known as aniridia type II protein (AN2) or oculorhombin, is a protein that in humans is encoded by the PAX6 gene.^[5] Pax6 is a transcription factor present during embryonic development. The encoded protein contains two different binding sites that are known to bind DNA and function as regulators of gene transcription. It is a key regulatory gene of eye and brain development. Within the brain, the protein is involved in development of the specialized cells that process smell. As a transcription factor, Pax6 activates and/or deactivates gene expression patterns to ensure for proper development of the tissue. Mutations of the Pax6 gene are known to cause various disorders of the eyes. Two common disorders associated with a mutation are: aniridia, the absence of the iris, and Peters' anomaly, thinning and clouding of the cornea. Scientists have created a "tae" model using mice during which time the mouse does not express Pax6. The "knockout" model is eyeless or has very underdeveloped eyes further indicating Pax6 is required for proper eye development.^[6]

Function

Fruitflies without the PAX6 gene have no eyes

PAX6 is a member of the Pax gene family which is responsible for carrying the genetic information that will encode the Pax-6 protein. It acts as a "master control" gene for the development of eyes and other sensory organs, certain neural and epidermal tissues as well as other homologous structures, usually derived from ectodermal tissues. However it has been recognized that a suite of genes is necessary for eye development, and therefore the term of "master control" gene may be inaccurate.^[7] Pax-6 is expressed as a transcription factor when neural ectoderm receives a combination of weak Sonic Hedgehog and strong TGF-Beta signaling gradients. Expression is first seen in the forebrain, hindbrain, head ectoderm and spinal cord followed by later expression in midbrain. This transcription factor is most noted for its use in the interspecifically induced expression of ectopic eyes and is of medical importance because heterozygous mutants produce a wide spectrum of ocular defects such as Aniridia in humans.^[8]

Pax6 serves as a regulator in the coordination and pattern formation required for differentiation and proliferation to successfully take place, ensuring that the processes of neurogenesis and oculogenesis are carried out successfully. As a transcription factor, Pax6 acts at the molecular level in the signaling and formation of the central nervous system. The characteristic paired DNA binding domain of Pax6 utilizes two DNA-binding domains, the paired domain (PD), and the paired-type homeodomain (HD). These domains function separately via utilization by Pax6 to carry out molecular signaling that regulates specific functions of Pax6. An example of this lies in HD’s regulatory involvement in the formation of the lens and retina throughout oculogenesis contrasted by the molecular mechanisms of control exhibited on the patterns of neurogenesis in brain development by PD. The HD and PD domains act in close coordination, giving Pax6 its multifunctional nature in directing molecular signaling in formation of the CNS. Although many functions of Pax6 are known, the molecular mechanisms of these functions remain largely unresolved.^[9]

Species distribution

Pax6 alterations result in similar phenotypic alterations of eye morphology and function across a wide range of species.

PAX6 protein function is highly conserved across bilaterian species. For instance, mouse PAX6 can trigger eye development in Drosophila melanogaster. Additionally, mouse and human PAX6 have identical amino acid sequences.^[10]

Genomic organisation of the PAX6 locus varies considerably among species, including the number and distribution of exons, cis-regulatory elements, and transcription start sites. The first work on genomic organisation was performed in quail, but the picture of the mouse locus is the most complete to date. This consists of 2 confirmed promoters (P0 and P1), 16 exons, and at least 6 enhancers. The 16 confirmed exons are numbered 0 through 13 with the additions of exon α located between exons 4 and 5, and the alternatively spliced exon 5a. Each promoter is associated with its own proximal exon (exon 0 for P0, exon 1 for P1) resulting in transcripts which are alternatively spliced in the 5’ un-translated region.

Of the four Drosophila Pax6 orthologues, it is thought that the eyeless (ey) and twin of eyeless (toy) gene products share functional homology with the vertebrate canonical Pax6 isoform, while the eyegone (eyg) and twin of eyegone (toe) gene products share functional homology with the vertebrate Pax6(5a) isoform. Eyeless and eyegone were named for their respective mutant phenotypes.

Isoforms

The vertebrate PAX6 locus encodes at least three different protein isoforms, these being the canonical PAX6, PAX6(5a), and PAX6(ΔPD). The canonical PAX6 protein contains an N-terminal paired domain, connected by a linker region to a paired-type homeodomain, and a proline/serine/threonine (P/S/T)-rich C-terminal domain. The paired domain and paired-type homeodomain each have DNA binding activities, while the P/S/T-rich domain possesses a transactivation function. PAX6(5a) is a product of the alternatively spliced exon 5a resulting in a 14 residue insertion in the paired domain which alters the specificity of this DNA binding activity. The nucleotide sequence corresponding to the linker region encodes a set of three alternative translation start codons from which the third PAX6 isoform originates. Collectively known as the PAX6(ΔPD) or pairedless isoforms, these three gene products all lack a paired domain. The pairedless proteins possess molecular weights of 43, 33, or 32kDa, depending on the particular start codon used. PAX6 transactivation function is attributed to the variable length C-terminal P/S/T-rich domain which stretches to 153 residues in human and mouse proteins.

Clinical Significance

Experiments in mice demonstrate that a deficiency in Pax-6 leads to decrease in brain size, brain structure abnormality leading to Autism, lack of iris formation or a thin cornea. Knockout experiments produced eyeless phenotypes reinforcing the gene’s role in eye development.^[8]

See also

• Gillespie syndrome
• https://commons.wikimedia.org/wiki/File:Eyeless_(Pax-6)-_Drosophila_Model.jpg
• Sigurd Snake-in-the-Eye

References

Further reading

External links

• PAX6 protein at the US National Library of Medicine Medical Subject Headings (MeSH)
• GeneReviews/NCBI/NIH/UW entry on Anophthalmia / Microphthalmia Overview
• GeneReviews/NCBI/NIH/UW entry on Aniridia
• OMIM entries on Aniridia
• Gene Expression Patterns from the Allen Brain Atlases